CYTOSINE METHYLATION CHANGES DURING NORMAL HEMATOPOIESIS AND IN ACUTEMYELOID-LEUKEMIA

The possible role of DNA methylation changes during several commitment steps of immature myeloid precursor cells toward functional, terminal ly differentiated phagocyte cells has previously been examined in the human myeloperoxidase (MPO) and macrophage colony-stimulating factor/c -fms genes using normal and transformed myeloid precursor cells. The h uman lysozyme (LZM) gene also provides a very useful model, because it s protein synthesis is continuously increased during myelopoiesis and thus most abundant in mature phagocytes. Several shifts toward LZM gen e demethylation coincide with upregulation of expression: activation o f expression in myeloid precursor cells and in primary cells of acute myeloid leukemia (AML) was associated with demethylation at a CpG dinu cleotide within the 5' flanking region; high-level expression in diffe rent types of normal mature phagocytic cells was associated with compl ete demethylation at two additional, intragenic CpG sites. Methylation changes occurring within the lysozyme gene could reflect transcriptio nal control of gene expression or maintenance of distinct maturation s tages during phagocyte development. They correlate with maturational a rrest and lysozyme gene expression in acute myeloid leukemias and may thus provide a genetic marker for the blocked differentiation of these neoplastic cells. Similar observations have been made for the MPO and c-fms genes.